Cellular and Molecular Basis of Cancer
Many factors are involved in causing and permitting the unregulated proliferation of cells that occurs in cancer.
(See also Overview of Cancer.)
Generation time is the time required for a cell to complete a cycle in cell division (see figure The cell cycle) and give rise to 2 daughter cells. Malignant cells, particularly those arising from the bone marrow or lymphatic system, may have a short generation time, and there usually are a smaller percentage of cells in G0 (resting phase). Initial exponential tumor growth is followed by a plateau phase when cell death nearly equals the rate of formation of daughter cells. The slowing in growth rate may be related to exhaustion of the supply of nutrients and oxygen for the rapidly expanding tumor. Small tumors have a greater percentage of actively dividing cells than do large tumors.
A subpopulation within many tumors, identified by surface proteins, may have the properties of primitive "normal" stem cells, as found in the early embryo. Thus, these cells are capable of entering a proliferative state. They are less susceptible to injury by drugs or irradiation. They are believed to repopulate tumors after surgical, chemical, or radiation treatment.
Cellular kinetics of particular tumors is an important consideration in the design of antineoplastic drug regimens and may influence the dosing schedules and timing intervals of treatment. Many antineoplastic drugs, such as antimetabolites, are most effective if cells are actively dividing, and some drugs work only during a specific phase of the cell cycle and thus require prolonged administration to catch dividing cells during the phase of maximal sensitivity.
As a tumor grows, nutrients are provided by direct diffusion from the circulation. Local growth is facilitated by enzymes (eg, proteases) that destroy adjacent tissues. As tumor volume increases, tumor angiogenesis factors, such as vascular endothelial growth factor (VEGF), are produced by tumors to promote formation of the vascular supply required for further tumor growth.
Almost from inception, a tumor may shed cells into the circulation. From animal models, it is estimated that a 1-cm tumor sheds > 1 million cells/24 h into the venous circulation. Circulating tumor cells are present in many patients with advanced cancer and even in some with localized disease. Although most circulating tumor cells die in the intravascular space, an occasional cell may adhere to the vascular endothelium and penetrate into surrounding tissues, generating independent tumors (metastases) at distant sites. Metastatic tumors grow in much the same manner as primary tumors and may subsequently give rise to other metastases.
Experiments suggest that the abilities to invade, migrate, and successfully implant and stimulate new blood vessel growth are all important properties of metastatic cells, which likely represent a subset of cells in the primary tumor.
Malignant cells typically manifest antigens that are interpretable as "non-self" by the immune system. Often, this leads to destruction of the malignant cells as with any foreign invader. This destruction may be complete, in which case the cancer never appears. However, some malignant cells have or acquire the ability to avoid detection and/or destruction by the immune system, allowing them to proliferate.
Although the immune system obviously has a protective role, it is not clear why people with congenital or acquired immune deficiencies have an increased risk of only some common cancers (eg, melanoma, renal cell carcinoma, lymphoma) and not others (eg, cancers of the lung, breast, prostate, colon). One consideration is that there has been little selective evolutionary pressure to refine the immune response to cancers that occur after the age of reproduction.
On the other hand, malignant cells have strong evolutionary pressure to develop ways to escape the immune system. One defense mechanism involves mimicking normal cells by expressing checkpoint proteins. Checkpoint proteins are cell-surface molecules that signal to circulating T-cells that the cell bearing them is normal and should not be attacked. An example is the PD-L1 protein, which is recognized by the PD-1 molecule on T cells; when PD-L1 binds to PD-1 on a T cell, that cell does not attack. Cancer therapy using monoclonal antibodies that block either PD-L1 or PD-1 (called checkpoint inhibitors) thus can allow the immune system to attack malignant cells previously protected by the presence of the PD-L1 protein. CTLA-4 is another checkpoint protein that prevents immune system attack and can be similarly blocked by an antibody. Because checkpoint proteins can be present on normal cells, checkpoint inhibitor therapy may also induce the immune system to attack those cells.
Another important advance in immune therapy involves using genetically engineered T-cells (referred to as chimeric antigen receptor T-cell [CAR-T] therapy). In this process, T cells are removed from a patient and genetically modified to express receptors containing a recognition domain for a specific tumor antigen coupled to intracellular signaling domains that activate the T cell. When the modified T cells are reinfused, they can attack cells bearing that specific tumor antigen.
Genetic mutations are responsible for the generation of cancer cells and are thus present in all cancers. These mutations alter the quantity or function of protein products that regulate cell growth and division and DNA repair. Two major categories of mutated genes are
Oncogenes are abnormal forms of normal genes (proto-oncogenes) that regulate various aspects of cell growth and differentiation. Mutation of these genes may result in direct and continuous stimulation of the pathways (eg, cell surface growth factor receptors, intracellular signal transduction pathways, transcription factors, secreted growth factors) that control cellular growth and division, cellular metabolism, DNA repair, angiogenesis, and other physiologic processes.
There are > 100 known oncogenes that may contribute to human neoplastic transformation. For example, the RAS gene encodes the ras protein, which carries signals from membrane-bound receptors down the RAS-MAPKinase pathway to the cell nucleus, and thereby regulates cell division. Mutations may result in the inappropriate activation of the ras protein, leading to uncontrolled cell growth. The ras protein is abnormal in about 25% of human cancers.
Other oncogenes have been implicated in specific cancers. These include
HER2 (amplified in breast and gastric cancer and less commonly in lung cancer)
BCRABL1 (a translocation of 2 genes that underlies chronic myeloid leukemia and some B-cell acute lymphocytic leukemias)
CMYC (Burkitt lymphoma)
NMYC (small cell lung cancer, neuroblastoma)
EGFR (adenocarcinoma of the lung)
EML4ALK (a translocation that activates the ALK tyrosine kinase and causes a unique form of adenocarcinoma of the lung)
Specific oncogenes may have important implications for diagnosis, therapy, and prognosis (see individual discussions under the specific cancer type).
Oncogenes typically result from
These changes may either increase the activity of the gene product (protein) or change its function. Occasionally, mutation of genes in germ cells results in inheritance of a cancer predisposition.
Genes such as TP53, BRCA1, and BRCA2 play a role in normal cell division and DNA repair and are critical for detecting inappropriate growth signals or DNA damage in cells. If these genes, as a result of inherited or acquired mutations, become unable to function, the system for monitoring DNA integration becomes inefficient, cells with spontaneous genetic mutations persist and proliferate, and tumors result.
As with most genes, 2 alleles are present that encode for each tumor suppressor gene. A defective copy of one gene may be inherited, leaving only one functional allele for the individual tumor suppressor gene. If a mutation is acquired in the functional allele, the normal protective mechanism of the 2nd normal tumor suppressor gene is lost.
The important regulatory protein, p53, prevents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal DNA to survive and divide. TP53 mutations are passed to daughter cells, conferring a high probability of replicating error-prone DNA, and neoplastic transformation results. TP53 is defective in many human cancers.
BRCA1 and BRCA2 mutations that decrease function increase risk of breast and ovarian cancer.
Another example, the retinoblastoma (RB) gene encodes for the protein Rb, which regulates the cell cycle by stopping DNA replication. Mutations in the RB gene family occur in many human cancers, allowing affected cells to divide continuously.
As with oncogenes, mutation of tumor suppressor genes such as TP53 or RB in germ cell lines may result in vertical transmission and a higher incidence of cancer in offspring.
Chromosomal abnormalities can occur through deletion, translocation, or duplication. If these alterations activate or inactivate genes that result in a proliferative advantage over normal cells, then a cancer may develop. Chromosomal abnormalities occur in most human cancers. In some congenital diseases (Bloom syndrome, Fanconi anemia, Down syndrome), DNA repair processes are defective and chromosome breaks are frequent, putting children at high risk of developing acute leukemia and lymphomas.
Most epithelial cancers likely result from a sequence of mutations that lead to neoplastic conversion. For example, the development of colon cancer in familial polyposis takes place through a sequence of genetic events: epithelium hyperproliferation (loss of a suppressor gene on chromosome 5), early adenoma (change in DNA methylation), intermediate adenoma (overactivity of the RAS oncogene), late adenoma (loss of a suppressor gene on chromosome 18), and finally, cancer (loss of a gene on chromosome 17). Further genetic changes may be required for metastasis.
Telomeres are nucleoprotein complexes that cap the ends of chromosomes and maintain their integrity. In normal tissue, telomere shortening (which occurs with aging) results in a finite limit in cell division. The enzyme telomerase, if activated in tumor cells, provides for new telomere synthesis and allows continuous proliferation of cancers.
Viruses contribute to the pathogenesis of some human cancers (see table Cancer-Associated Viruses). Pathogenesis may occur through the integration of viral genetic elements into host DNA. These new genes are expressed by the host; they may affect cell growth or division or disrupt normal host genes required for control of cell growth and division. Alternatively, viral infection may result in immune dysfunction, leading to decreased immune surveillance for early tumors. HIV infection increases the risk of a number of cancers (see Cancers Common in HIV-Infected Patients).
Hepatitis-B or -C virus
Human T-lymphotropic virus-1
Bacteria may also cause cancer. Helicobacter pylori infection increases the risk of several kinds of cancer (gastric adenocarcinoma, gastric lymphoma, mucosa-associated lymphoid tissue [MALT] lymphoma).
Parasites of some types can lead to cancer. Schistosoma haematobium causes chronic inflammation and fibrosis of the bladder, which may lead to cancer. Opisthorchis sinensis has been linked to carcinoma of the pancreas and bile ducts.
Ultraviolet radiation may induce skin cancer (eg, basal and squamous cell carcinoma, melanoma) by damaging DNA. This DNA damage consists of formation of thymidine dimers, which may escape excision and resynthesis of a normal DNA strand. Patients with inherent defects in DNA repair (eg, xeroderma pigmentosum) or immunity suppressed by drugs or underlying disease are particularly prone to skin cancers from ultraviolet exposure.
Ionizing radiation is also carcinogenic. For example, survivors of the atomic bomb explosions in Hiroshima and Nagasaki have a higher-than-expected incidence of leukemia and other cancers. Similarly, exposure to therapeutic irradiation may lead to leukemia, breast cancer, sarcomas and other solid cancers years after exposure. Exposure to x-rays for diagnostic imaging studies is thought to increase risk of cancer (see Risks of Medical Radiation). Industrial exposure (eg, to uranium by mine workers) is linked to development of lung cancer after a 15- to 20-yr latency. Long-term exposure to occupational irradiation or to internally deposited thorium dioxide predisposes people to angiosarcomas and acute nonlymphocytic leukemia.
Radon, a radioactive gas that is released from soil, increases the risk of lung cancer, especially in smokers. Normally, radon disperses rapidly into the atmosphere and causes no harm. However, when a building is placed on soil with high radon content, radon can accumulate, sometimes producing sufficiently high levels in the air to cause harm. In exposed people who also smoke, the risk of lung cancer is further increased.
Estrogen in oral contraceptives may slightly increase the risk of breast cancer, but this risk decreases over time. Estrogen and progestin used for hormone replacement therapy also increase the risk of breast cancer.
Diethylstilbestrol (DES) increases the risk of breast cancer in women who took the drug and increases the risk of vaginal cancer in daughters of these women exposed before birth.
Long-term use of anabolic steroids may increase the risk of liver cancer.
Treatment of cancer with chemotherapy drugs alone or with radiation therapy increases the risk of developing a second cancer, as do immunosuppressive drugs given for organ transplantation.
Chemical carcinogens can induce gene mutations and result in uncontrolled growth and tumor formation (see table Common Chemical Carcinogens). Other substances, called co-carcinogens, have little or no inherent carcinogenic potency but enhance the carcinogenic effect of another agent when exposed simultaneously.
Common Chemical Carcinogens
Certain substances consumed in the diet can increase the risk of cancer. For instance, a diet high in fat has been linked to an increased risk of colon, breast, and possibly prostate cancer. People who drink large amounts of alcohol are at higher risk of developing various cancers, including head and neck and esophageal cancer. A diet high in smoked and pickled foods or in meats cooked at a high temperature increases the risk of developing stomach cancer. People who are overweight or obese have a higher risk of cancer of the breast, endometrium, colon, kidney, and esophagus.
Chronic skin, lung, GI, or thyroid inflammation may predispose to development of cancer. For example, patients with long-standing inflammatory bowel disease (ulcerative colitis) have an increased risk of colorectal carcinoma. Sunlight and tanning light exposure increases the risk of skin cancers and melanoma.
Immune system dysfunction as a result of inherited genetic mutation, acquired disorders, aging, or immune-suppressing drugs interferes with normal immune surveillance of early tumors and results in higher rates of cancer. Known cancer-associated immune disorders include
Ataxia-telangiectasia (acute lymphocytic leukemia [ALL], brain tumors, gastric cancer)
Wiskott-Aldrich syndrome (lymphoma, ALL)
X-linked agammaglobulinemia (lymphoma, ALL)
Immune deficiency due to immune-suppressing drugs or HIV infection (large cell lymphoma, cervical cancer, head and neck cancer, Kaposi sarcoma)
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